According to the immune surveillance hypothesis, the immune system is continuously sensitized against developing tumours, where experimental evidence strongly supports this notion. The identification of specific tumour antigens has created new possibilities for tumour immunotherapy and many immunotherapeutic approaches are now being translated into clinical trials. Among these, adoptive transfer of tumour antigen-specific lymphocytes seems particularly promising. These attempts have, so far, usually been based on either mononuclear cells from peripheral blood or tumour infiltrating lymphocytes (TIL) separated from fresh tumour specimens. In recent trials, treatment of patients with malignant melanoma with autologous transfer of expanded TILs, objective response rates of up to 51% has been reported. TIL cells are few, they are frequently unresponsive (anergic) due to immunosuppressive mechanisms from the tumour creating long periods for expansions to occur (several months). Furthermore, the protocols have been aiming towards the expansion of CD8+ cytotoxic T cells and the cells have been reintroduced into patients preconditioned with chemotherapy and in addition the patients have been treated with high doses of interleukin-2 to provide survival of CD8+ T cells.
Gallbladder Cancer
Gallbladder cancer is a relatively uncommon disease with approximately 9 000 new cases per year in the United States. Gallbladder cancer is very aggressive and commonly spreads to the liver, pancreas or stomach.
Patients diagnosed with gallbladder cancer face a grim prognosis with overall survival being only 5%-10%. In cases where the cancer has spread to other organs, long term survival is very rare.
The most common form of treatment today is surgical removal of the gallbladder and lymph node dissection.
Hepatocellular Carcinoma
Hepatocellular carcinoma is a malignant tumor of the liver. The disease accounts for approximately 19 000 new cases each year in the United States. Infection with the Hepatitis B och C viruses has been established as a major cause of the disease.
Prognosis of the disease is generally very poor. The most common form of treatment is surgical resection of the tumor, in cases where possible. If the cancer cannot be removed, the disease is usually deadly within 3 to 6 months.
Ovarian Cancer
Cancer of the ovaries accounts for approximately 27 000 new cases and 15 000 deaths per year in the United States. There are over 25 major types of ovarian neoplasms, the most common being serous adenocarcinoma.
Prognosis is very dependant upon in which stage the disease is diagnosed. For early stages, long-term survival can reach over 90%. Survival is dramatically decreased with later diagnosis, and overall five year survival for all stages is less than 40%.
Surgery is today the preferred form of treatment, with chemotherapy used after surgery to treat any residual disease.
Small Intestine Cancer
Small intestine cancer, or cancer of the small bowel, accounts for only a minute proportion of all gastrointestinal malignancies. There are approximately 6 000 new cases per year in the United States. Adenocarcinoma is the most common subtype of small intestine cancer, accounting for approximately half of the cases.
Inflammatory disease of the small bowel has been established as a major risk factor for small intestine cancer.
Surgery is today the only known effective treatment, and is possible in approximately two thirds of all patients. Five year survival rates for patients who undergo surgical resection of the tumor is 40-60%.
Breast Cancer
With almost 180 000 new cases per year, breast cancer is the most common type of cancer among women in the United States, and the second most common cause of cancer death (approximately 40 000 deaths per year). Over the last 50 years, the incidence of the disease has slowly increased.
Despite much research, the cause of breast cancer is still poorly understood.
For staging and prognosis, evaluation of tumor cell presence in regional lymph nodes is commonly done in conjunction with surgery.
Along with surgery, treatment alternatives include chemotherapy, hormonal therapy, radiotherapy and immune therapy.
Lung Cancer
Carcinoma of the lung is the most common cause of cancer death worldwide and in the United States. More than 200 000 new cases are developed each year in the United States, and about 160 000 will die from the disease.
Cigarette smoking is by far the leading cause of lung cancer, accounting for approximately 85% of all cases. All subtypes of lung cancer are associated with cigarette smoking, but the strongest connection is with squamos cell carcinoma and small cell carcinoma. In cases where the patient is a non-smoker, the most common type is adenocarcinoma.
Patients with surgically resectable tumors have the best prognosis. Factors correlated with adverse prognosis include large tumor size and metastases to lymph nodes.
Mesothelioma
Mesothelioma is a neoplasm of mesothelial cells, which is most common in the pleura. Approximately 2 000 patients are affected each year in the United States.
More than 80% of patients are reported to have been exposed to asbestos. The latency period between exposure and appearance of the disease is usually 20-40 years.
There are no known effective treatments today, and the prognosis is dismal.
Kidney Cancer
The most common type of kidney cancer is renal cell carcinoma, followed by renal pelvis carcinoma. Each year, there are in total more than 50 000 new cases of kidney cancer in the United States, and kidney cancer is the cause of more than 12 000 deaths.
In patients where the cancer has not spread to other organs, kidney cancer can normally be cured with surgery. If the cancer has spread to lymph nodes or other organs, commonly the lung, bone or liver, long-term is reduced dramatically to only around 10%.
Prostate Cancer
Prostate cancer is a very common malignancy among older men. Patients younger than 50 years constitute less than 1% of all new cases (about 220 000 each year) in the United States. Prostate cancer accounts for about 25 000 deaths every year in the U.S.
Almost all of primary prostatic tumors are adenocarcinomas. The most common metastatic sites are the lymph nodes, bonea, lung and liver.
Radiation therapy and surgical removal of the prostate are the most common forms of treatment today.
Carcinoid Cancers
Carcinoid is an often malignant type of tumor originating in the cells of the neuroendocrine system. The majority of carcinoid tumors are found in the appendix, small intestine or rectum. The tumor can also originate in other locations, including the lungs, pancreas, bronchus, gallbladder ovary and testis.
Surgical removal of the tumor is the standard treatment when possible and is often curative. Carcinoid tumors are generally slow-growing. In patients with distant metastases, the median survival is about two years.
Leiomyosarcoma
Leiomyosarcoma is a rare type of malignant neoplasm of smooth muscle. It can arise almost anywhere in the body, but most commonly in the uterus, abdomen or pelvis.
Radiation therapy and chemotherapy are usually ineffective against leiomyosarcoma. Surgical resection of the tumor can be curative. The five year survival rate for leiomyosarcoma is about 30%.
The immune system often appears informed about tumours, as shown by an accumulation of immune cells at tumour sites, which correlates with improved prognosis. Immuno-competent cells respond to “danger” signals, which can be provided of growing tumours as a consequence of the genotoxic stress of cell transformation and disruption of the surrounding microenvironment. Under ideal conditions, these signals will induce inflammation, activate innate effector cells with antitumour activity, and stimulate professional antigen-presenting cells (APCs), particularly dendritic cells (DCs), to engulf tumour-derived antigens and migrate to draining lymph nodes to trigger an adaptive response by T and B lymphocytes. Thus, the immune system is capable of recognizing and eliminating tumour cells but unfortunately tumours often interfere with the development and function of immune responses. However, recent advances in cellular and molecular immunology suggest strategies, which may prevent antitumour responses. Briefly, the presence of a tumour indicates that the developing cancer was able to avoid detection or to escape or to overwhelm the immune response. Progressing tumours often exhibit strategies that promote evasion from immune recognition. Examples are physical exclusion of immune cells from tumour sites, poor immunogenicity due to reduced expression of major histocompatibility complex (MHC) or costimulatory proteins, and disruption of natural killer (NK) and natural killer T (NKT) cell recognition. Further, some tumours prevent triggering of an inflammatory response by secreting proteins such as interleukin 10 (IL-10) or vascular endothelial growth factor (VEGF) that interfere with DC activation and differentiation, or by blocking the production of proinflammatory molecules by increasing expression of the STAT3 protein. Even if a response is induced, tumour cells may escape elimination by losing targeted antigens, rendering tumour-reactive T cells anergic, inducing regulatory T cells, or specifically deleting responding T cells. The tumour that finally develops reflects selection of poorly immunogenic and/or immune-resistant malignant cells.
In the adjuvant setting, tumour immunotherapy offers an appealing alternative to traditional cytostatics. One strategy has been to expand and activate NK cells in vitro with out specific antigen by culture with IL-2 followed by infusion of large numbers of these NK cells back into patients alone or with high doses of IL-2. This approach, or administration of high doses of IL-2 to expand and activate NK cells entirely in vivo, has yielded antitumour activity and remission in a subset of patients (Rosenberg S A et al., J Natl Cancer Inst 85, 622, 1993). However, life-threatening toxicity often develops, largely due to the release of tumour necrosis factor (TNF) from activated NK cells.
Thus, it is obvious that there is still a need for an effective and at the same time safe treatment of gall bladder cancer, hepato cellular cancer, ovarian cancer, small intestine cancer, lung cancer, mesothelioma, breast cancer, kidney cancer, pancreas cancer, prostate cancer, carcinoid cancer, leiomyosarcoma, or metastasis thereof.